The halichondrins are polyether macrolides, originally isolated from the marine sponge Halichondria okadai by Uemura, Hirata, and coworkers. Several additional members, including halistatin, were also isolated from marine sponges. This class of natural products displays interesting structural diversity at two main sites, one being the oxidation state at C10, C12, and C13 of the C8-C14 polycycle, and the other being the length of the carbon backbone. Based on the elements providing structural diversity, this class of natural products has been grouped into the norhalichondrin, halichondrin, and homohalichondrin series with several representative sub-groups (see FIG. 1). While norhalichondrins A-C, homohalichondrins A-C, and halichondrins B & C have all been isolated from the natural sources, halichondrin A has never been isolated from natural sources.

Due to their intriguing structural architecture and extraordinary in vitro and in vivo anti-proliferative activity, the halichondrins have received much attention from the scientific community. Indeed, Eisai recently received FDA approval for the halichondrin derivative eribulin (HALAVEN®) for treatment of metastatic breast cancer, further highlighting the importance these natural products derivatives. Thus, further research focused on the discovery of novel agents within this structural class is likely to provide new anti-proliferative agents with improved efficacy or safety. Furthermore, new synthetic methods that streamline the preparation of these natural products or related derivatives are important given the structural complexity of the halichondrin backbone.